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Nonhypercalcemic 1,25‐(OH) 2 D 3 analogs potently induce the human osteocalcin gene promoter stably transfected into rat osteosarcoma cells (ROSCO‐2)
Author(s) -
Morrison Nigel A.,
Eisman John A.
Publication year - 1991
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.5650060815
Subject(s) - osteocalcin , transfection , reporter gene , biology , vitamin d and neurology , alkaline phosphatase , endocrinology , osteosarcoma , cell culture , medicine , calcium , gene , chemistry , gene expression , cancer research , biochemistry , enzyme , genetics
1,25‐Dihydroxyvitamin D 3 [1,25‐(OH) 2 D 3 ] is the active hormonal form of vitamin D 3 and has potent effects on bone and calcium regulation. Over the past decade it has become apparent that 1,25‐(OH) 2 D 3 has other effects on cellular proliferation that potentially could be developed for therapy in human malignancy. Since the hypercalcemic effects of 1,25‐(OH) 2 D 3 have limited that use in the human, novel nonhypercalcemic analogs of 1,25‐(OH) 2 D 3 have been synthesized. The molecular mechanism of this divergence in these antiproliferative and calcium‐regulating actions is unexplained. We have previously examined the human bone‐specific gene osteocalcin as a model of the molecular mechanisms of vitamin D action in bone and have shown that induction of the osteocalcin gene by 1,25‐(OH) 2 D 3 is mediated through an unique and complex palindromic region of the promoter similar to but distinct from those of other steroid hormone‐responsive elements. Using an osteosarcoma cell line permanently transfected with the vitamin D‐responsive promoter of the human osteocalcin gene linked to a “reporter” gene, we have shown that there is a dose‐dependent induction of CAT activity by 1,25‐(OH) 2 D 3 and that the potencies of vitamin D metabolites and analogs are comparable to those found in other vitamin D bioassays. Furthermore, vitamin D analogs, including MC‐903, 22‐oxa‐1,25‐(OH) 2 D 3 , and Δ22–1,25S,26‐trihydroxyvitamin D 3 , which effect cellular differentiation but lack hypercalcemic activity in vivo, exhibit osteocalcin promoter inductive actions virtually identical to those of 1,25‐(OH) 2 D 3 . Consideration of these and other data support the hypothesis that the divergent effects of such analogs on differentiation and calcium homeostasis reflect pharmacokinetic differences in vivo rather than distinct 1,25‐(OH) 2 D 3 ‐sensitive pathways.